As a major microvascular complication of diabetes, the incidence of diabetic kidney disease (DKD) is increasing progressively, especially in the elderly. Early intervention is essential for the prevention and treatment of DKD. Organ crosstalk has a strong association in the progression of DKD, while C-X-C motif chemokine ligand 1 (CXCL1), a chemokine plays a critical role in the liver-kidney axis. Our previous studies found that fucoidan interventions prevented the progression of long-term high-fat diet-induced DKD, while also improving liver damage. However, the precise mechanisms through which fucoidan influences CXCL1 associated with liver-kidney crosstalk in DKD are not yet fully understood. The purpose of this study was to investigate the possible mechanism of fucoidan on the high-fat diet-induced DKD. Sixty male C57BL/6J mice were randomly divided into control, DKD, metformin (MET), low dose fucoidan (LFC, 50 mg/kg/d), middle dose fucoidan (MFC, 100 mg/kg/d), and high dose fucoidan (HFC, 200 mg/kg/d) groups for 24 weeks. Compared to the DKD group, HFC significantly reduced the urine creatinine ((555.06 ± 87.67) μg/L vs. (429.62 ± 33.29) μg/L; P < 0.05) and glomerular hypertrophy ((61.46 ± 4.54) mmol/L vs. 54.86±2.66 mmol/L; P < 0.05). Moreover, HFC treatment significantly reduced the CXCL1 level in the liver ((37.51 ± 6.70) pg/ng prot vs. (63.64 ± 7.15) pg/ng prot; P < 0.05) and kidney ((38.77 ± 8.55) pg/ng prot vs. (56.76 ± 7.50) pg/ng prot; P < 0.05) compared to the DKD group. Fucoidan treatment inhibited macrophage recruitment (P < 0.05) and modulated the expression of IL-6 and TNF-α in the kidney of DKD mice. Moreover, the expression of cyclic GMP-AMP synthase, stimulator of interferon genes, and nuclear factor kappa-B in the HFC group was significantly lower compared with the DKD group. Collectively, these findings suggest that fucoidan exerts a protective effect against DKD induced by a high-fat diet through the crosstalk between the liver and kidney, based on CXCL1.